Chinese Journal of Tissue Engineering Research ›› 2020, Vol. 24 ›› Issue (4): 625-630.doi: 10.3969/j.issn.2095-4344.1881
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Feng Yong, Zhao Yanxu, Zhang Minze
Received:
2019-04-23
Revised:
2019-04-30
Accepted:
2019-06-22
Online:
2020-02-08
Published:
2020-01-07
Contact:
Zhang Minze, Chief physician, Master’s supervisor, Department of Trauma Reconstruction, Yan'an University Affiliated Hospital, Yan'an 716000, Shaanxi Province, China
About author:
Feng Yong, Master candidate, Department of Trauma Reconstruction, Yan'an University Affiliated Hospital, Yan'an 716000, Shaanxi Province, China
CLC Number:
Feng Yong, Zhao Yanxu, Zhang Minze. Human amniotic membrane, drugs, and growth factors prevent adhesion after repair of tendon injury [J]. Chinese Journal of Tissue Engineering Research, 2020, 24(4): 625-630.
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2.2 药物 2.2.1 抗炎药 张乐等[14]通过SD大鼠实验证实纳米化姜黄素能明显减轻肌腱损伤后的局部炎性反应,从而改善肌腱术后粘连程度并且不降低肌腱的愈合强度。吲哚美辛、塞来昔布等抗炎药[15],可以减低损伤肌腱周围的炎症反应,减少肌腱与周围组织的粘连。布洛芬可抑制环氧化酶1和环氧化酶2并减少肌腱粘连[5]。 2.2.2 维生素C 维生素C可参与成纤维细胞合成胶原纤维已被公认,若降低腱周围维生素C的浓度,可减少腱结缔组织增生并长入腱内,从而为肌腱内源性愈合争取时间。张鹏[16]采用链霉素复合缓释降解膜可降低腱旁结缔组织内维生素C浓度,从而抑制腱周结缔组织增生,使腱内增生快于腱周结缔组织增生,防止腱周结缔组织增生长入腱内,减轻粘连形成。肌腱损伤后过度的氧化应激反应会干扰细胞存活和募集,特别是减少对愈合至关重要的中性粒细胞和巨噬细胞的迁移。HUNG 等[17]应用维生素C作为抗氧化剂,局部注射于鸡肌腱损伤术后模型中,5 g/L维生素C组和50 g/L维生素C组均可减轻肌腱粘连,但5 g/L组减轻粘连效果更好,他们推断,这可能是过量的维生素C抑制了血管再生时所需的适当的氧化应激反应。 2.2.3 转化生长因子β抑制剂 5-氟尿嘧啶可以抑制细胞有丝分裂,周智等[18]将80例指曲肌腱损伤患者随机分为2组,实验组在肌腱缝合后局部给予5-氟尿嘧啶浸泡,并用大清止血膜覆盖,对照组生理盐水冲洗,在术后4,8周分别观察两组患者肌腱总主动活动度变化,实验组活动度均优于对照组且差异有显著性意义,在术后3个月测定两组患者转化生长因子β1、基质金属蛋白酶9表达水平,实验组均少于对照组且差异有显著性意义。LOISELLE等[19]研究证实基质金属蛋白酶9基因表达可引起小鼠肌腱粘连,即基质金属蛋白酶9是一种导致肌腱粘连的酶。XIA等[20]发现转化生长因子β1会导致术后粘连组织的形成。5-氟尿嘧啶可以通过抑制组织中转化生长因子β1、基质金属蛋白酶9的表达,起到防止粘连的作用。壳聚糖可以通过高表达miR-29b及下调TGF-β1/Smad3水平减轻肌腱粘连[21],还有研究表明,壳聚糖可以通过sirtuin 1信号传导途径防止兔屈肌腱修复期间的粘连[22]。转化生长因子β3也可通过TGF-β/Smad信号通路调节Smad3和Smad7蛋白,从而减少外源性瘢痕[23]。 2.2.4 其他 YURDAKUL SIKAR等[24]研究发现透明质酸凝胶只能减少重建后的肌腱粘连,而Seprafilm防粘连膜既可以减少重建后的肌腱粘连,又可以减少未重建的肌腱粘连。几丁糖、聚乳酸应用于防止肌腱粘连已有大量成熟的研究[25-26]。 2.3 生长因子 2.3.1 血小板衍生生长因子 血小板衍生生长因子是贮存在血小板α颗粒中的一种碱性蛋白,有血小板衍生生长因子AA、血小板衍生生长因子AB、血小板衍生生长因子BB 3种二聚体形式。血小板衍生生长因子BB可以刺激G0/G1期的血管平滑肌细胞、成纤维细胞、胶质细胞进入分裂周期,但发挥这一作用有剂量依赖性[27]。林樾[28]将血小板衍生生长因子BB基因转染的大鼠肌腱细胞注射到跟腱损伤模型大鼠跟腱断端,维持了局部血小板衍生生长因子BB的局部浓度,克服了血小板衍生生长因子BB直接应用易被体内蛋白水解酶破坏的特点,证明了血小板衍生生长因子BB可以促进肌腱的内源性愈合,改善肌腱粘连。 2.3.2 血管内皮生长因子 血管内皮生长因子又叫血管通透因子,可促进新生血管的形成和血管通透性的增加。何爱咏等[29]研究指出,血管内皮生长因子可以促进肌腱的内源性愈合,且50 ng和100 ng组较10 ng组更明显;但是徐红立等[30]给予兔屈肌腱损伤模型局部应用血管内皮生长因子中和抗体,肌腱血管内皮生长因子表达降低,粘连程度改善。结合肌腱的内外源性愈合理论,外源性愈合是导致肌腱粘连的主要原因,并由此推断血管内皮生长因子主要是通过肌腱的外源性愈合发挥作用。血管内皮生长因子中和抗体可能是通过减轻局部炎症,减少肉芽组织中的血管,从而抑制血管内皮生长因子引起的肉芽组织过度增生,减轻局部粘连。柯尊山等[31]研究表明血小板衍生生长因子BB和血管内皮生长因子基因在损伤后的肌腱组织中不表达,在粘连组织中仅少量表达。结合上文,可以认为在病理情况下,血小板衍生生长因子BB和血管内皮生长因子基因只会在损伤肌腱周围表达,起到促使肌腱周围粘连组织形成的作用,而不干预肌腱本身的生长,若人为给予一定浓度的血小板衍生生长因子BB或血管内皮生长因子在损伤肌腱上,则促进肌腱生长的作用更明显,因此而加速内源性愈合,一定程度上抑制了肌腱的外源性愈合。而给予血小板衍生生长因子BB或血管内皮生长因子中和抗体在损伤肌腱周围,则抑制了它们促进粘连组织形成的作用。 2.3.3 碱性成纤维细胞生长因子 碱性成纤维细胞生长因子具有刺激血管生成、成纤维细胞增殖、迁移及分泌胶原的作用[32]。CHEN等[33]研究发现内源性碱性成纤维细胞生长因子在兔跟腱损伤愈合早期起一定的作用。柯尊山等[31]研究发现碱性成纤维细胞生长因子在损伤后肌腱组织中的表达高于粘连组织,说明碱性成纤维细胞生长因子在以促进内源性愈合为主的同时,有轻微的促使粘连形成的作用。THOMOPOULOS等[34]研究表明内源性碱性成纤维细胞生长因子能促进肌腱细胞生长。沙德峰等[35]在大鼠随机实验中,给予A组跟腱损伤模型缝合处包裹碱性成纤维细胞生长因子复合缓释降解膜,B组缝合处只给予缓释降解膜包裹,而C组缝合处不做任何处理,结果显示:A组缝合处不仅成纤维细胞和胶原纤维明显多于B、C组,且A组腱周粘连程度远较B、C组轻,可见碱性成纤维细胞生长因子促进肌腱内源性愈合的同时,预防了肌腱与周围组织的粘连,而这一作用主要是通过加速肌腱的内源性愈合来实现。TANG 等[36]将碱性成纤维细胞生长因子基因通过腺相关病毒载体2转移至鸡屈肌腱,显著增加了肌腱的愈合强度,但不增加粘连形成。 2.3.4 胰岛素样生长因子1 TSUZAKI等[37]研究证明胰岛素样生长因子1能缩短肌腱细胞的形成周期;任强 等[38]研究发现,在跟腱损伤后的第4天,跟腱外的胰岛素样生长因子1出现强势表达,从而导致跟腱外源性愈合的迅速启动。此时跟腱内部胰岛素样生长因子1表达较弱,即内源性表达未完全启动,他们由此推断,是否可以在肌腱损伤后的第4天,在肌腱内部注射胰岛素样生长因子1或在腱周注射胰岛素样生长因子1抗体,使肌腱内部的胰岛素样生长因子1远高于肌腱外部,从而达到促进内源性愈合,预防肌腱粘连的目的。 2.3.5 转化生长因子β1 转化生长因子β在人体有3种同分异构体,其中转化生长因子β1与肌腱损伤后修复关系最密切。转化生长因子β可以促进Ⅰ型胶原纤维的产生,而Ⅰ型胶原纤维的形成是导致肌腱粘连的重要因素[39]。夏长所等[40]研究兔屈趾肌腱Ⅱ区伤口愈合过程中转化生长因子β1基因表达的变化,发现转化生长因子β1在正常和损伤肌腱均有表达,损伤肌腱表达更高,损伤后第1天就开始表达,第2,3周达到高峰,主要集中在肌腱缝合处的肌腱和腱外膜,伤口周围的腱鞘组织中转化生长因子β1表达水平更高,且各时间点腱鞘内表达均高于肌腱,由此可以推断转化生长因子β1主要促进肌腱的外源性愈合。张志敏等[41]研究也证实抗转化生长因子β1抗体预防术后肌腱粘连,且不影响肌腱正常愈合。然而,在WU等[42]最新研究中发现抑制转化生长因子β1的功能,虽然会改善肌腱滑动功能,减少肌腱粘连,但同时也会使该肌腱最大抗拉强度较对照组少12%-24%,如何做到既能抑制肌腱粘连,又不影响肌腱功能的恢复,还有待于新的研究成果的出现。 2.4 其他 术后早期功能锻炼能改善肌腱滑动功能,增强肌腱收缩力,但是需要术中对肌腱进行牢固缝合[43]。应用网状缝合线缝合后[44],肌腱平均屈曲强度是4-0编织线缝合后肌腱的2倍,平均最大收缩强度也比后者高80%,可以为术后早期功能锻炼提供力学支持。MENG等[45]对损伤肌腱进行氢处理,可减轻局部炎症反应及肌腱粘连。细胞外基质支架也可用于减轻肌腱粘连,且可以减轻术后疼痛[46]。 "
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